Abstract
Many kinds of 3, 3-disubstituted-1-(2-chloroethyl)-1-nitrosourea derivatives (V) of aldopentoses were synthesized and tested for antitumor activities against leukemia L1210 and Ehrlich ascites carcinoma. The reaction of aldopentoses with primary amines followed by treatment with 2-chloroethyl isocyanate usually gave a mixture of two or three structural isomers of glycosylureas (III'). Complete isomerization into thermodynamically stable glycopyranosylureas (III) was observed when the mixture of the isomers was dissolved in formic acid. Glycopyranosylureas (III) were nitrosated with 4 equivalents of dinitrogen tetroxide followed by treatment with methanol to give the corresponding nitrosoureas (V) in good yields. A large number of nitrosoureas (V) were remarkably active against leukemia L1210 and Ehrlich ascites carcinoma and showed greater therapeutic ratios than the positive controls, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, 3-[(4-amino-2-methyl-5-pyrimidinyl) methyl]-1-(2-chloroethyl)-1-nitrosourea, and 1-(2-chloroethyl)-3-(β-D-glucopyranosyl)-1-nitrosourea. In particular, many of the arabinopyranosyl-nitrosoureas had large therapeutic ratios (more than fifty) against leukemia L1210 and even larger ones (more than a hundred) against Ehrlich ascites carcinoma. These nitrosoureas (V) appear to be activated nonenzymatically by attack of the hydroxyl group of the sugar moiety on the carbonyl group to give the cyclic carbamate (VII) without generation of the isocyanate.
